Aging is associated with poor B cell function and decreased production of protective antibodies to which both systemic and B cell intrinsic inflammation contribute. Aging is also associated with increased production of autoimmune antibodies. Our studies in mice have shown that the adipose tissue (AT), which increases in size with aging, contributes to systemic and B cell intrinsic inflammation, reduced B cell responses and secretion of autoimmune antibodies, the specificity of which is unknown. In this grant we propose toconfirm and extend inhumans our results obtained in miceand identify several uninvestigated mechanisms through which obesity accelerates and/or exacerbates age effects on human B cells and induces the secretion of autoantibodies. We hypothesize that 1) obesity-associated chronic inflammation is a major contributor to B cell defects/depressed humoral immune responses and accelerates/exacerbates age-related defects in B cells; 2) the AT contributes to the generation of pathogenic B cells characterized by the secretion of pro-inflammatory mediators and autoimmune antibodies; 3) identified inflammatory molecules/pathways may be targeted to reduce pathogenic B cells at least in vitro. In Aim 1 we will determine how pro- and anti-inflammatory immune cells are generated in the subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (and in the blood as control) of individuals of different ages, and the cellular and molecular pathways which contribute to this. In Aim 2 we will evaluate the effects of SAT and VAT in the induction of pathogenic/autoimmune B cells. We will measure secretion and autoimmune specificity of antibodies by B cells from the AT as compared to the blood; NK cytotoxicity as a possible mechanism to release autoantigens and induce autoantibody production; autoantigen presentation to B cells by macrophages/NKT cells. In Aim 3 we will target inflammatory molecules/pathways with the goal of reducing local inflammation and the pathogenic function of B cells at least in vitro. The proposed treatments/mechanisms will offer a solid empirical basis for future translational/clinical studies.